The Expression of Stem Cell Marker LGR5 and Its Coexpression with Β-Catenin in Sporadic Colorectal Carcinoma and Adenoma: A Comparative Immunohistochemical Study.

Background: LGR5 is one of the most important stem cell markers for colorectal cancer (CRC), as it potentiates Wnt/Β-catenin signaling. The well-characterized deregulation of Wnt/Β-catenin signaling that occurs during adenoma/carcinoma sequence in CRC renders LGR5 a hopeful therapeutic target. We assessed the immunohistochemical expression of LGR5 and Β-catenin in normal colonic and tumorous lesions with a clinicopathological correlation. Methods: Tissue blocks and clinical data of 50 selected cases were included: 8 from normal mucosa, 12 cases of adenoma, and 30 cases of CRC, where sections were cut and re-examined and the immunohistochemical technique was conducted using anti-LGR5 and anti-Β-catenin to measure the staining density. Results: There was no expression of LGR5 in normal mucosa compared to samples of adenoma and CRC samples. The association analysis showed that CRC specimens were more likely to have strong LGR5 and Β-catenin expressions than the other two groups (p = 0.048 and p < 0.001, respectively). Specimens with high-grade dysplastic adenoma were more likely to express moderate-to-strong expression of LGR5 and Β-catenin (p = 0.013 and p = 0.036, respectively). In contrast, there were no statistically significant associations between LGR5 and Β-catenin expression with grade and stage. Conclusion: These results suggest and support the possible role of LGR5 as a potential marker of cancer stem cells in sporadic colorectal carcinogenesis in addition to a prognostic value for LGR5 and Β-catenin in adenomatous lesions according to immunohistochemical expression density. A potential therapeutic role of LGR5 in CRC is suggested for future studies based on its role in pathogenesis.

Design and Synthesis of Pyridazine Containing Compounds with Promising Anticancer Activity.

Certain pyridazine containing compounds 2a-f, 3a, b, 4a, b, 5a, b, 6a and b were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were screened for their cytotoxic activity in vitro on colon cancer cell line (HCT-116) and breast cancer cell line (MCF-7). In addition, the antitumor activity of the synthesized compounds was tested in vivo against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. The in vitro vascular endothelial growth factor receptor (VEGFR) enzyme inhibition assay was carried out for the most active compounds at a single dose of 10 µM. The obtained results revealed that compound 5b, which showed potent cytotoxic activity against HCT-116 also, exhibited the highest inhibition in the VEGFR kinase assay (92.2%).

Synthesis of New N1-Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin.

A series of pyrazoline derivatives 2a-e, 3a-e and 4a-e structurally related to combretastatin A4 (CA-4) were synthesized and characterized by spectroscopic means and elemental analyses. In these compounds, the cis double bond of CA-4 was replaced with the pyrazoline ring aiming to enhance the cytotoxic effects displayed by CA-4 and to prevent the cis/trans isomerization that is associated with inactivation of CA-4. The cytotoxic activity of all new compounds was investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by the most active compounds 3d, 4a and e was evaluated. The cytotoxicity of 4e was correlated with induction of apoptosis and caspase-3 activation in vitro thus indicating the apoptotic pathway of anticancer effect of these compounds. Furthermore, in vivo evaluation of the synthesized compounds was carried out against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. Compounds 2c, 3a and e showed significant reduction in tumor weight, and about 2-4 fold increase in caspase-3 expression.

Synthesis and biological evaluation of new pyrazolone-pyridazine conjugates as anti-inflammatory and analgesic agents.

A new series of pyrazolone-pyridazine conjugates 3 and 4a-l were synthesized and characterized by spectroscopic means and elemental analyses. All compounds were tested in vivo for their anti-inflammatory and analgesic properties against diclofenac, as reference compound. The synthesized compounds were also evaluated for their ability to inhibit the production of certain inflammatory cytokines such as TNF-α and IL-6 in serum samples. The ulcerogenic potential of the synthesized compounds was also determined. IC50 values for inhibition of COX-1 and COX-2 enzymes were investigated in vitro for the most active candidates. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Among the synthesized derivatives, compounds 4c and 4e showed good analgesic and anti-inflammatory activities with lower ulcer index than the reference drug.

Effect of treatment of chronic hepatitis c virus patients with direct-acting anti-retroviral drugs on semen and hormonal parameters.

Objective: Hepatitis C virus (HCV) infection is known to influence the seminal and hormonal parameters of infected men. This study was performed to assess the effects of HCV clearance using direct-acting antiviral (DAA) agents on semen and hormonal parameters. Methods: A total of 50 patients with chronic HCV were enrolled, and conventional semen analysis was performed according to World Health Organization guidelines. Basal levels of total testosterone, free testosterone (FT), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin, and sex hormone-binding globulin (SHBG) were assessed before and 3 months after treatment with DAAs. Results: Following DAA treatment, statistically significant increases were observed in sperm motility and the proportion of grade A sperm. Additionally, the percentage of abnormal forms was significantly decreased after treatment (p=0.000). However, no significant differences were observed in semen volume, concentration, or total sperm count. Sex hormone analysis of patients after DAA treatment revealed significant increases in FT, LH, and FSH levels, along with significant decreases in SHBG, prolactin, and E2 levels. Conclusion: Following HCV clearance, we noted an improvement in sperm motility and an increase in the percentage of sperm with normal morphology. Treatment with DAAs was also associated with increased levels of FT and LH, along with decreased levels of SHBG, prolactin, and E2.

Synthesis of new nicotinic acid derivatives and their evaluation as analgesic and anti-inflammatory agents.

A series of 2-substituted phenyl derivatives of nicotinic acid 4a-l were synthesized and evaluated for their analgesic and anti-inflammatory activities. Compounds including 2-bromophenyl substituent, 4a, c, and d, proved to display distinctive analgesic and anti-inflammatory activities in comparison to mefenamic acid as a reference drug. Compound 4c could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic profile. Effect of the compounds 4a-l on the serum level of certain inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 was also determined.

Synthesis and biological evaluation of new heteroaryl carboxylic acid derivatives as anti-inflammatory-analgesic agents.

A series of nicotinic acid derivatives structurally related to niflumic acid and certain pyridazine-containing compounds have been synthesized and characterized by analytical and spectral data. All compounds were screened for their potential analgesic and anti-inflammatory activities. The compounds which displayed analgesic and anti-inflammatory activities were tested for ulcerogenicity and screened for in vivo inhibition of certain inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Compounds 1c, 2a, 2b, and 5a have shown potent analgesic and anti-inflammatory activities.

Sun-Exposed versus Sun-Protected Cutaneous Basal Cell Carcinoma: Clinico-Pathological Profile and p16 Immunostaining.

INTRODUCTION: Although widespread, BCC is still relatively poorly understood in regards to pathogenesis and prognosis, particularly the lesions formed on anatomical sites away from sun exposure. With the aim of deepening our understanding of the pathogenesis and clinico-pathological correlations of BCCs, we conducted this study. METHODS: Tissue blocks and data of 52 Egyptian patients diagnosed with BCC were retrieved for clinical information and inclusion criteria, then re-examined histologically; p16 immunostaining was carried out and evaluated for analysis and comparison between the two groups, i.e., sun-exposed and sun-protected. RESULTS: Sex, age, clinical suspicion, tumor size, recurrence status, and histologic variants did not show a significant difference between the sun-protected and sun-exposed groups; however, the mean ages recorded were 67.2 vs. 62.7 for the sun-protected and sun-exposed groups, respectively. A total of 52% of BCCs were positive for p16. The sun-protected lesions showed p16 positivity in 61% of cases, whereas 49% of the sun-exposed lesions were positive with no significant difference. There was a significant difference in p16 expression between the recurrent and non-recurrent lesions. CONCLUSIONS: A significant difference was seen in the case of cancer recurrence, where all the recurrent BCCs in this study demonstrated negative p16 immunostaining of the primary lesions; however, the positively stained cases in total were 52% of BCCs. The mean patient age of the sun-protected group was much higher than in previous peer studies. We assume that the biological, prognostic, and clinical aspects of p16 protein expression in BCCs are still far from being clearly understood. Further studies are highly recommended, with more focus on its role in the pathogenesis and the prognostic factors.

Clinico-Pathological Features and Immunohistochemical Comparison of p16, p53, and Ki-67 Expression in Muscle-Invasive and Non-Muscle-Invasive Conventional Urothelial Bladder Carcinoma.

INTRODUCTION: The identification of bladder detrusor muscle invasion in urothelial cancer is essential for prognosis and management. We studied the clinical, histological, and immunohistochemical expression of p16, p53, and Ki-67 in urothelial detrusor muscle-invasive bladder cancer (MIBC) and urothelial non-detrusor muscle-invasive bladder cancer (NMIBC) in Egyptian patients. METHODS: Sixty-two bladder urothelial cancer cases obtained through TURBT were included and divided into two groups: (MIBC, stage T2) and NMIBC (T1). Tissue blocks were recut and re-examined microscopically; then, the immunostaining of p16, p53, and Ki-67 was performed to compare both groups and evaluate the 13% cut-off for Ki-67, 20% for p53, and p16 intensity in various conditions aided by telepathology technology. RESULTS AND CONCLUSION: Hematuria was the main clinical first presentation, with no significant difference between either group. The mean age was 61.6 years, with male predominance (52 males and 10 females). The absence of papillary histological pattern was associated with a higher stage, including detrusor muscle invasion (p = 0.000). The overall average percent of p53 immunostaining was 12.9%, revealing no significant difference between MIBC and NMIBC when a cut-off of 20% was implicated. The Ki-67 expression was correlated with higher grade and muscle invasion; however, no association was found with the other two markers' expression. The negative immunostaining of p16 was associated with low grade and NMIBC in the case of the preservation of the papillary pattern. We recommend further studies on the cut-off of widely used markers and more immunohistochemical and genetic studies on the p16(INK4A), taking into consideration the histological pattern of conventional carcinomas.

Synthesis of certain 2-substituted-1H-benzimidazole derivatives as antimicrobial and cytotoxic agents.

A series of 2-substituted-1H-benzimidazole derivatives were synthesized and evaluated for antimicrobial, antifungal and cytotoxic activities. The results showed that all tested compounds showed potent antimicrobial activity against some species of Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi) and fungi (Candida albicans) with minimum inhibitory concentrations (MICs) lower than 0.016 µg/mL. In contrast, all tested compounds were inactive against Staphylococcus aureus (Gram-positive bacterium). The final targets were also tested for their antitumor activity in vitro on cervical carcinoma (HeLa) cell line. Eight of the test compounds displayed more potent cytotoxic effect than doxorubicin at nanomolar concentrations. Compounds 2c and 3c exerted the strongest cytoyoxic effect with IC(50) 15 and 13 nM, respectively.

Dose-response association between vitamin D deficiency and atopic dermatitis in children, and effect modification by gender: a case-control study.

BACKGROUND: Vitamin D is a regulatory factor for immunity and skin barrier functions. It is hypothesized to be linked to atopic dermatitis (AD) which is characterized by interaction between epidermal barrier dysfunction and dysregulation of skin immune functions. METHODS: One hundred AD patients and one hundred and one normal controls were collected from outpatient clinic based on their clinical condition, both had measurement of 25-hydroxyvitamin D [25(OH)D]. We assessed the relationship between 25(OH)D deficiency and AD prevalence using adjusted Poisson regression model. RESULTS: Serum 25(OH)D levels were significantly lower in cases than controls (mean 35.1 versus 22.6 ng/mL, p < .001). The unadjusted prevalence ratios (PRs) (95% CI) for AD for comparing participants with intermediate and deficient vitamin D levels to those with optimal levels were 3.11 (1.91, 5.06) and 4.77 (2.99, 7.60), respectively. The association did not materially change after adjusting for potential confounders. In the fully adjusted analysis stratified by gender, PRs for AD for comparing male participants with intermediate and deficient vitamin D levels to those with optimal levels were 3.38 (1.21, 9.40) and 5.20 (1.91, 14.13), respectively, whereas in the female participants were 1.32 (0.96, 1.83) and 1.49 (1.04, 2.14), respectively (p-interaction <.001). CONCLUSION: In this case-control study in children, we found a statistically significant dose-response association between vitamin D deficiency and AD. We also observed a statistically significant effect modification of this association by gender. Further research is recommended to study this association longitudinally, and to examine whether treating vitamin D deficiency may potentially improve AD. Key points Question: Can atopic dermatitis be associated with vitamin D deficiency? Finding: Serum 25(OH)D levels were significantly lower in cases with AD than in controls. Prevalence ratios for comparing male participants with intermediate and deficient vitamin D levels to those with optimal levels were 3.38 (1.21, 9.40) and 5.20 (1.91, 14.13), respectively, whereas in the female participants were 1.32 (0.96, 1.83) and 1.49 (1.04, 2.14), respectively (p-interaction <.001). Meaning: vitamin D deficiency is associated with AD in children, effect modification of this association by gender was also observed.

The impact of active vitamin D administration on the clinical outcomes of acne vulgaris.

Acne vulgaris is one of the most common chronic inflammatory skin disorder affecting millions of people worldwide. Vitamin D deficiency has a role in various inflammatory skin diseases as acne. This study aimed to investigate the serum level of 25 hydroxy vitamin D in acne patients and to assess the efficacy and safety of active vitamin D in management of acne. This study was conducted on 100 patients with acne and 100 healthy controls, then the 100 acne patients were randomized to either the study group that received 0.25ug alfacalcidol daily or the placebo group that received oral placebo during the 3 months study period. Serum levels of 25-hydroxy-vitamin D were significantly lower in acne patients than in healthy control and were inversely correlated to the severity of acne. After alfacalcidol administration, the study group showed significant higher level of 25(OH) D levels (p < .05) compared to placebo group. In addition, median serum level of IL6 and TNFα significantly decreased (p < .05) in the study group in comparison to placebo group and as compared to their baseline results. Acne patients are more commonly to have vitamin D deficiency as compared to healthy people and hence, alfacalcidol might have a beneficial role in the acne management with no reported side effects.

Case report: hematemesis could be an unusual presentation of cow's milk protein allergy in children in Egypt.

Cow's milk protein allergy (CMPA) is common in infants with variable clinical presentation including varied gastrointestinal manifestation. Cow's milk protein allergy chiefly, involving occurs in children below the age of 3 years, successful therapy depends on completely eliminating cow's milk proteins (CMP) from the child's diet. Ideally, with the replacement of hypo or an allergenic food. Symptoms suggestive of CMPA may be encountered in approximately 5 to 15% of infants emphasizing the importance of controlled elimination/milk challenge procedures. We report on an Egyptian male infant, who developed frequent attacks of hematemesis when begin to eat foods other than breast milk including cow's milk and its dairy products at the age of three months. Possible cow's milk protein allergy was suspected. Further diagnostic work-up was done including: Hb, hematocrit, MCV: iron, ferritin, CRP, occult blood in stools, antibodies to H-pylori and upper GIT endoscopy and biopsy from snip of duodenal mucosa. Measurement of serum cow milk protein specific IgE by radio allegro sorbent test (RAST) technique (immune CAP specific IgE method) and results revealed cow's milk protein allergy. It is concluded that cow's milk protein allergy should be considered in cases of hematemesis presented in early infancy in infants who fed cow's milk early and that hematemesis should be added to the list of clinical presentation of CMPA.